Acta Demato-Venereologica 98-2CompleteContent | Page 20

INVESTIGATIVE REPORT
251
Search for RASA1 Variants in Capillary Malformations of the Legs
in 113 Children: Results from the French National Paediatric Cohort
CONAPE
Annabel MARUANI 1–3# , Marine DURIEUX-VERDE 1,2# , Juliette MAZEREEUW-HAUTIER 4 , Olivia BOCCARA 5 , Ludovic MARTIN 6 ,
Christine CHIAVERINI 7 , Catherine ESCHARD 8 , Nathalie BENETON 9 , Pierre VABRES 10 , Xavier BALGUERIE 11 , Patrice PLANTIN 12 ,
Didier BESSIS 13 , Sébastien BARBAROT 14 , Ali DADBAN 15 , Catherine DROITCOURT 16 , Aline BERTHELOT 17 , Gérard LORETTE 1,2 ,
Sophie LEDUCQ 1,2 , Mahtab SAMIMI 1,2 , Christian ANDRES 1,17 , Agnès CAILLE 1,3 , Patrick VOURC’H 1,17 ; and Groupe de Recherche
de la Société Française de Dermatologie Pédiatrique
University François Rabelais Tours, 2 CHRU Tours, Department of Dermatology, 3 CHRU Tours, Clinical Investigation Center-INSERM 1415,
Tours, 4 Department of Dermatology, University Hospital Center of Toulouse, Toulouse, 5 Department of Dermatology and Reference Center
for Genodermatoses and Rare Skin Diseases (MAGEC), University Hospital Necker-Enfants Malades, Paris, Departments of Dermatology,
6
University Hospital Center of Angers, Angers, 7 University Hospital Center of Nice, Nice, 8 University Hospital Center of Reims, Reims, 9 Hospital
Center of le Mans, le Mans, 10 University Hospital Center of Dijon, Dijon, 11 University Hospital Center of Rouen, Rouen, 12 Hospital Center of
Quimper, Quimper, 13 University Hospital Center of Montpellier, Montpellier, 14 University Hospital Center of Nantes, Nantes, 15 University Hospital
Center of Amiens, Amiens, 16 University Hospital Center of Rennes, Rennes, and 17 INSERM U930, CHRU Tours, Laboratory of Biochemistry
and Molecular Biology, Tours, France 
#
These authors contributed equally and should be considered as first authors.
1
Patients with an inherited autosomal-dominant dis-
order, capillary malformation–arteriovenous malfor-
mation (CM-AVM), frequently have mutations in Ras
P21 protein activator 1 (RASA1). The aims of this
study were to determine the prevalence of germline
RASA1 variants in a French multicentre national cohort
of children, age range 2–12 years, with sporadic oc-
currence of capillary malformation (CM) of the legs,
whatever the associated abnormalities, and to identify
genotype–phenotype correlates. DNA was extracted
from leukocytes in blood samples, purified and ampli-
fied, and all exons of the RASA1 gene were analysed.
Among 113 children analysed, 7 had heterozygous
variants (6.1%). Four different variants were iden-
tified; 2 were new. In children with RASA1 variants,
CMs were more frequently bilateral and multifocal. In
conclusion, RASA1 variants are rarely found in children
with sporadic CM of lower limbs without CM-AVM syn-
drome. CMs in this study were heterogeneous, and no
disease-causing relationship could be proven.
Key words: RASA1; mutations; variants; polymorphism; capil-
lary malformations; vascular anomalies.
Accepted Nov 2, 2017; Epub ahead of print Nov 7, 2017
Acta Derm Venereol 2018; 98: 251–255.
Corr: Annabel Maruani, CHRU Tours, Hospital Trousseau, Department of
Dermatology, Avenue de la République, FR-37044, Tours Cedex 9, France.
E-mail: annabel.maruani @univ-tours.fr
O
ur knowledge of the genetic causes of vascular
malformations has increased considerably in recent
years. In capillary malformations (CMs), post-zygotic ac-
tivating mutations of G protein subunits alpha Q (GNAQ)
and alpha 11 (GNA11) have been found in affected skin of
patients with facial port-wine stains in Sturge-Weber syn-
drome or phacomatosis pigmentovascularis (1, 2). Post-
zygotic activating phosphatidylinositol-4,5-bisphosphate
3 catalytic (PIK3CA) mutations also account for a
number of capillary/lymphatic malformations as part of
the CLOVES and macrocephaly-CM syndromes (3, 4).
Cutaneous CMs might be associated with germline mu-
tations in the Ras P21 protein activator 1 gene (RASA1)
as part of the autosomal dominant syndrome, capillary
malformation-arteriovenous malformation (CM-AVM)
(5, 6).
CM-AVM syndrome was initially described as a
combination of very suggestive and typical multifocal
cutaneous CMs (small, round CMs, with pale halos),
associated with high-flow superficial lesions, arteriove-
nous fistulas (AVFs) or cerebral AVMs (6). However,
mutations in RASA1 have been reported in 3 families
of patients with CM, but without AVM (7). Similarly,
Wooderchak-Donahue reported RASA1 mutations asso-
ciated with hereditary CM, with or without AVF or AVM
in 8 subjects (8). In sporadic cases, germline RASA1
mutations have been identified in the peripheral blood
of 1 patient with Sturge-Weber syndrome (9).
RASA1 mutations were found to be responsible for
aberrant lymphatic architecture and functional abnorma-
lities other than CM in mice and humans (10). RASA1
encodes the 120-RasGAP protein involved in the RAS-
MAPK signalling pathway that controls proliferation,
migration, and survival of various cell types, including
vascular endothelial cells. The P120-RasGAP protein
converts active GTP-bound Ras into inactive GDP-bound
Ras and has been involved in vascular development in
RASA1-/- mice (11). Loss of function mutations in RASA1
in humans are associated with abnormal angiogenic re-
modelling of the primary capillary plexus, with vascular
anomalies, not compensated by other RasGAPs, such as
RASA2, RASAL, or NF1 (6, 12).
Since 2010 we have implemented a multicentre natio-
nal cohort (CONAPE) from 14 French tertiary centres of
paediatric dermatology specialized in vascular anoma-
lies, including 120 children aged 2–12 years with CMs
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2018 Acta Dermato-Venereologica.
doi: 10.2340/00015555-2835
Acta Derm Venereol 2018; 98: 251–255